In schizophrenia, gene mutations disrupt key proteins

"This degree of convergence from several studies is unprecedented in schizophrenia genetics and tells us that for the first time we have a handle on one of the core brain processes that is disrupted in the disorder," says Mike Owen. (Credit: Daniela Vladimirova/Flickr)

Genetic mutations seen in people with schizophrenia, but not in their parents, disrupt specific sets of proteins that have related functions in the brain.

These pathways are involved in modulating the strength of connections between nerve cells and play important roles in brain development, learning, memory, and cognition.

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The findings, published in Nature, are from the largest genetic study of its kind. An international team led by researchers at Cardiff University examined DNA blood samples from 623 sufferers and their parents.

“We already had evidence from previous work in Cardiff supporting the importance of these pathways but the new findings, together with those from another study published in the same issue of Nature, confirm the importance of these and related sets of proteins,” according to Professor Mike Owen from Cardiff University’s MRC Centre for Neuropsychiatric Genetics and Genomics, who co-led the research.

“This degree of convergence from several studies is unprecedented in schizophrenia genetics and tells us that for the first time we have a handle on one of the core brain processes that is disrupted in the disorder,” he adds.

As well as identifying how genetic mutations impact on brain function the findings also indicate an overlap with the causes of other neurodevelopmental disorders, including autism and intellectual disability.

Professor Mick O’Donovan from Cardiff University’s MRC Centre, who jointly led the research, adds: “The fact we’ve been able to identify a degree of overlap between the underlying causes of schizophrenia and those in autism and intellectual disability suggests that these disorders might share some common mechanisms and lends further weight to calls for research that integrates findings across multiple disorders.

“We need research that takes into account genetics, cognitive science, imaging, and other sources of information rather than relying solely on clinical definitions for psychiatric disorders.”

Related study

Patrick Sullivan, a professor of genetics and psychiatry at the University of North Carolina School of Medicine, is a co-author of the second study, which compared the gene sequences from 2,500 people in Sweden with schizophrenia to 2,500 healthy individuals from the same population.

“This landmark study shines bright light on a part of the genome we’ve never been able to see before,” says Sullivan. “It looks like schizophrenia is less a disease of changes in the structure of proteins, and more a problem of the amounts of proteins.”

The two current studies looked for mutations that were effectively invisible in previous studies: they detected changes at the scale of single nucleotides—substitutions, insertions, or deletions of individual bases or “letters” in the genetic code.

“Despite the considerable sample sizes, no individual gene could be unambiguously implicated in either study. Taken as a group, however, genes involved in neural function and development showed greater rates of disruptive mutations in patients,” explains Shaun Purcell of the Broad Institute of MIT and Harvard, who played key roles in both studies. “That finding is sobering but also revealing: it suggests that many genes underlie risk for schizophrenia and so any two patients are unlikely to share the same profile of risk genes.”